Our long-term goal is to understand which roles BRCA1 plays in cellular activities and how its impairment leads to breast tumorigenesis. Although no BRCA1 mutation is found in the majority of sporadic breast cancers, its expression is down-regulated in 20-61% of the cases, extending the relevance of BRCA1 deficiency to the general breast cancer pathogenesis. We have previously elucidated the role of BRCA1 in DNA damage response and guarding genome stability through interacting with repair machinery proteins. However, BRCA1 as a full tumor suppressor must act to modulate cellular proliferation and differentiation. How BRCA1 executes such activities has not been fully developed. Previously, we identified a novel BRCA1-interacting protein, ZBRK1, which binds to a specific DNA sequence found in a subset of BRCA1 target genes, thus establishing a means by which BRCA1 is physically and functionally tethered to particular regulatory loci and serves as a co-repressor. We have also demonstrated that depletion of BRCA1, CtIP or ZBRK1 by RNAi in mammary epithelial cells (MECs) 3-D culture, a close mimicry of an in vivo environment, leads to MEC proliferation and impairs mammary acinus differentiation by altering the expression of genes including ANG1 (Angiopoietin1), HMGA2 (High Mobility Group AT-hook 2) and others. These results strongly support that BRCA1 has a critical role in governing MEC proliferation and differentiation. Importantly, factors secreted from normal differentiating MEC are able to inhibit breast cancer cell growth. Among these, we have identified IL17E (IL25) that kills breast cancer cells through caspase-mediated cell death pathway and inhibits tumorigenicity with non-detectable toxicity in animals, and BMP10 that also specifically inhibits breast cancer cell growth but not normal MEC. Based on these advances, we propose three specific aims to test the hypothesize that BRCA1 and its interacting partners coordinately regulate functionally diverse genes involved in proliferation and differentiation of MECs and modulating the microenvironment as follows: Aim 1. To study the mode and consequence of transcriptional repression of ANG1 and HMGA2 mediated by BRCA1/ZBRK1; Aim 2. To elucidate regulatory modes of BRCA1-mediated, but ZBRK1 independent, transcriptional modulation of FGF2, RFC1, TIP30 and TFDP1; and Aim 3. To characterize factors of IL-17E and BMP10 secreted from differentiating MEC that kill breast cancer cells. We expect that the results obtained from this proposal will contribute significant to the future diagnosis and treatment of breast cancer because these BRCA1-modulated genes are oncogenic or tumor-suppressive in nature and have potential diagnostic and prognostic values. Especially, these natural factors that specifically suppress proliferation and induce breast cancer cell death will potentially provide a novel tumor dormancy therapy for treating breast cancer.